Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC(C)([O-:9])C.[K+].S=[C:13]1[CH:18]([CH2:19]C)[CH2:17][C@@H:16]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[CH2:15][N:14]1C(O)=O.Cl>C(O)C>[NH2:4][C:3]1[N:5]=[C:19]([OH:9])[C:18]2[CH2:17][C@@H:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)[CH2:15][NH:14][C:13]=2[N:2]=1
Reactant: CCC1C[C@@H](CCc2ccc(Br)cc2)CN(C(=O)O)C1=S
Reactant: CC(C)(C)[O-]
Reactant: N=C(N)N
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Nc1nc(O)c2c(n1)NC[C@H](CCc1ccc(Br)cc1)C2
Temperature: 90 °C
Yield: 80.3 %

Procedure:
A suspension of 740 mg (7.77 mmol) of guanidine hydrochloride in 5 mL of ethanol was neutralized by addition of 950 mg (7.77 mmol) of potassium tert-butoxide. The precipitated potassium chloride was filtered with filter aid and washed with an additional 5 mL of ethanol. A solution of 720 mg (1.94 mmol) of (3RS, 5R)-2-thioxo-3-ethylcarboxy-5-[2-(4-bromophenyl)ethyl]piperidine in 5 mL ethanol was added to the liltrate and this solution was reduced to a volume of 2-3 mL under vacuum. The solution was heated in an oil bath (T=90° C.) under a stream of nitrogen for 2 h. After cooling to ambient temperature, the mixture was subjected to further vacuum evaporation. The resulting solid was suspended in water, sonicated to form a uniform suspension, and neutralized to pH 7 by addition of 1N aq. HCl. The resulting suspension was heated to about 90° C. for 15 min, then cooled to ambient temp. and filtered. The product was dried in vacuo (10 torr), affording 544 mg (80%) of (R)-(-)-2-amino-4-hydroxy-6-[2-(4-bromophenyl)ethyl]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine mp 275°-283° C., [α]589 -30.9° (c 1, DMF), 1H NMR (DMSO-d6) δ9.70 (bs, 1H), 7.40 (d, J=8.3 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 6.23 (d, J=8.3 Hz, 2H), 5.96 (s, 2H), 3.15 (bd, J=11 Hz, 1H), 2.45 (m, 2H), 1.78 (dd, J=8.6, 15.1, 1H), 1.50 (m, 3H); IR (KBr) 3400, 3343, 1678, 1642 cm-1 ; MS (EI), m/z 350 (78), 348 (72), 166 (100), 165 (95), 164 (31), 151 (68), 139 (19). The NMR spectrum was identical with that of a sample of (S)-(+)-3 obtained as described in U.S. Pat. No. 5,008,391.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[OH-].[Na+].[O-:26]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>CO.O.OO>[CH3:10][C:6]1[CH:5]=[N:4][C:3]([CH2:11][S+:12]([O-:26])[C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)=[C:2]([CH3:1])[C:7]=1[O:8][CH3:9]
Reactant: O=S([O-])([O-])=S
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
2 g of 2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]thio]-5-methoxy-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 1.88 g of 45% NaOH in 14 ml water was added while stirring. 0.09 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.74 g H2O2 (50% aqueous solution), and further diluted with 10 ml. of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes while stirring. 10 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Omeprazole with a yield of about 88% (LC purity>95%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH:25]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][CH2:12][C@@H:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:31]4[CH2:32][CH2:33][N:28]([CH:25]5[CH2:27][CH2:26]5)[CH2:29][CH2:30]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: C1CN(C2CC2)CCN1
Reactant: N#CC1(NC(=O)C2CCC(S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2CC[C@@H](S(=O)(=O)c3ccc(N4CCN(C5CC5)CC4)cc3Cl)C2)CC1

Procedure:
The title compound was synthesized in analogy to Example 80, from rac-(1S,35)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide and 1-cyclopropyl-piperazine to afford the desired product as an off-white solid. MS (EI): 477.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:27][CH2:28][CH2:29]Cl)[O:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][O:20]2)=[CH:15][CH:14]=1.O>CN(C)C=O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH2:27][CH2:28][CH2:29][O:3][C:4]3[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=3)[C:7]#[N:8])[O:20][CH2:21][C:22]([CH3:25])([CH3:26])[CH2:23][O:24]2)=[CH:17][CH:18]=1
Reactant: CC1(C)COC(CCCCl)(c2ccc(Br)cc2)OC1
Reactant: N#Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)COC(CCCOc2cccc(C#N)c2)(c2ccc(Br)cc2)OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
236 mg (5.9 mmol) of sodium hydride (oily, 60%) was stirred in dimethylformamide. 691 mg (5.8 mmol) of 3-hydroxybenzonitrile was added thereto under cooling with ice. After stirring at room temperature for 30 minutes, a solution of 2 g (5.75 mmol) of 2-(4-bromophenyl)-2-(3-chloropropyl)-5,5-dimethyl-1,3-dioxane in dimethylformamide was added to the reaction mixture, and they were stirred at 100° C. overnight. Water was added to the mixture. After the extraction with ethyl acetate, the organic layer was washed with 1 N aqueous sodium hydroxide solution and saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: ClCc1ccncc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(Cc3ccncc3)C2=O)CC1
Yield: 68 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride (2.4 equivalents) and 4-(chloromethyl)pyridine hydrochloride, to give the desired product as a light yellow foam (68%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:28]=O>COCCOC>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:28]=[C:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (1.37 g (9.68 mmol) in anhydrous 1,2-dimethoxyethane (10 ml) is added sodium methoxide (0.575 g, 10.60 mmol) in one portion, followed by stirring at this temperature for 10 minutes. To this slurry is then added a second solution of 4-bromo-4′-chloro-biphenyl-3-carbaldehyde (2.60 g, 8.80 mmol) in 1,2-dimethoxyethane (10 ml) dropwise. When addition is complete the reaction mixture is stirred at 0° C. for a further 1 hour, then quenched with 2M hydrochloric acid (50 ml). After stirring for an additional 1 hour the solution is diluted with diethyl ether, the two phases separated, and the aqueous phase further extracted with diethyl ether (×2). The combined organics are further washed with brine, then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to afford 4-[1-(4-bromo-4′-chlorobiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (3.40 g, 92%) as a yellow gum.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OCC)OCC.[H-].[Na+].[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=O)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=[CH:3][C:2](=[O:1])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOP(=O)(CC(=O)c1ccccc1)OCC
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=CC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diethyl (2-oxo-2-phenylethyl)phosphonate (0.96 mL,1.1 g, 4.4 mmol) was added in one portion to a stirred suspension of sodium hydride (60% oil dispersion, 158 mg, 3.95 mmol) in THF (20 mL). After 15 min. at RT, the clear solution was cooled in an ice bath and 1-(benzyloxycarbonyl)-4-piperidinecarboxaldehyde (840 mg, 3.40 mmol) was added in THF (1.0 mL) with additional THF (2×1.0 mL) for rinsing. Stirring was continued for a total of 2 h, with slow warming to RT. The mixure was then partitioned between ether (120 ml) and 2.5 N NaOH (60 mL). The organic layer was washed with saturated aq. NaCl (60 mL), dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel eluting with 85:15 v/v to 80:20 v/v hexanes/EtOAc to give 0-95 g of the title compound as a colorless syrup: 1H NMR (400 MHz) δ 7.82 (d, J=8, 21), 7.57 (t, J=8, 1H), 7.48 (t, J=8, 2H), 7.39-7.29 (m, 51), 6.99 (dd, J=15, 6, 1H), 6.87 (dd, J=15, 1, 1H), 5.15 (s, 2H), 2.97-2.82 (m, 2H), 2.50-2.39 (m, 1H), 1.89-1.77 (m, 2H), 1.54-1.39 (m, 2H); ESI-MS 367 (M+NH3+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=CC=2N=N1.CN(C=O)C.C1(CN)CC1>C1COCC1>[CH:37]1([CH2:36][NH:32][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:6]([Cl:26])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:25])[CH2:39][CH2:38]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)NCC3CC3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 22.1 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.080 g, 0.152 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.130 g, 0.406 mmol), TEA (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and 1-cyclopropylmethanamine (0.044 g, 0.406 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 0.220 (q, J=4.5 Hz, 2H), 0.44 (q, J=6.6 Hz, 2H), 1.01 (m, 1H), 1.51 (s, 6H), 3.02 (s, 2H), 3.19 (t, J=6.0 Hz, 2H), 7.22 (s, 1H), 7.77 (s, 1H), 8.43 (s, 2H), 10.99 (s, 1H), 11.40 (s, 1H); MS [M+H]+: 446.27.
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(CC)CC.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C=O)C>[NH3:5].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[CH2:39][CH2:40][N:41]([C:1]([O:2][CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]2)=[O:22])[CH2:42][CH2:43]1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(N2CCN(C(=O)OCCN3CCN(C)CC3)CC2)c1
Product: N
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.3 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 866 mg, 2.8 mmol) was dissolved in DMF (25 mL). NEt3 (0.5 mL, 3.6 mmol) and 4-(2,5-dimethyl-phenyl)piperazine (580 mg, 3.1 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL) and washed with 1M aq Na2CO3 solution (5×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 200:8:1 mixture of DCM:EtOH:NH3) to give 2-(4-methylpiperazin-1-yl)ethyl 4-(2,5-dimethyl-phenyl)piperazine-1-carboxylate (274 mg, 27%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH2:7][C@@H:8]([N:12]1[CH:16]=[C:15]([C:17]([NH2:19])=[O:18])[N:14]=[CH:13]1)[C@@H:9]([OH:11])[CH3:10].[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:23]1[C:24]([C:2]2[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=2)[O:5][CH2:6][CH2:7][C@@H:8]([N:12]2[CH:16]=[C:15]([C:17]([NH2:19])=[O:18])[N:14]=[CH:13]2)[C@@H:9]([OH:11])[CH3:10])=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: C[C@H](O)[C@@H](CCOc1cccc(Br)c1)n1cnc(C(N)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[C@H](O)[C@@H](CCOc1cccc(-c2cc3ccccc3s2)c1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
To a solution of 1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide in DME (5 ml) was added Pd(PPh3)4 (29.3 mg, 0.025 mmol)at ambient temperature under N2. After stirring for 20 min., benzothiophene-2-boronic acid (54.2 mg, 0.304 mmol) and a solution of Na2CO3 (40.3 mg, 0.38 mmol) in H2O (1 ml) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and partitioned between ethyl acetate (20 ml) and H2O. The organic layer was washed successively with saturated NaHCO3 aqueous solution, H2O and then brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with chloroform/methanol (100:1 to 20:1) to give 1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide (41) (66.9 mg, 62.6%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:19])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:26](=[O:28])[CH3:27])=[C:14]([CH3:19])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid (1.1 g) was dissolved in 10 ml of pyridine, then 2 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure. The residue was purified by column chromatography using 20 g of silica gel. The desired fractions were combined and evaporated to dryness under reduced pressure and the residue was recrystallized from aqueous ethanol to give 0.7 g of 4-chloro-1-(4-acetoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless needles, m.p. 200°-203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[O:12][C:13]2[C:14](=[C:16]([C:20](O)=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:15]=1.Cl.Cl.[NH2:25][C@H:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:28]12[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29]1)[C@H:26]([NH:25][C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:13]3[O:12][C:11]([C:4]4[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=4[O:2][CH3:1])=[N:15][C:14]=13)=[O:21])[CH2:27]2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)c(OC)c1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cccc3o2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
A mixture of 2-(2,4-dimethoxyphenyl)benzo[d]oxazole-4-carboxylic acid (100 mg, 0.33 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (66 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg, 0.66 mmol) and 1-hydroxybenzotriazole (89 mg, 0.66 mmol) in DMF (1.5 mL) was stirred at room temperature for 5 min, then triethylamine (0.18 mL, 1.32 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dimethoxyphenyl)benzoxazole-4-carboxamide (61 mg, 46%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.68 (d, J=7.0 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 6.68-6.65 (m, 2H), 4.32-4.26 (m, 1H), 4.00 (s, 3H), 3.92 (s, 3H), 3.50 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.86 (m, 4H), 2.83 (dd, J=14.5, 4.5 Hz, 1H), 2.22-2.17 (m, 1H), 2.10-1.98 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 408 (M+H); HPLC 96.1% (AUC), tR=12.82 min.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[OH2:11].[CH2:12]=O.Cl>C(O)(C)C>[OH:11][CH2:12][C:4]1[O:3][C:2]([CH2:9][OH:10])=[CH:1][C:6](=[O:7])[C:5]=1[OH:8]
Reactant: O=c1cc(CO)occ1O
Reactant: C=O
Reactant: O
Agent: Cl
Solvent: CC(C)O
Product: O=c1cc(CO)oc(CO)c1O
Reaction time: 12 h

Procedure:
50 g (0.35 mol) of kojic acid (1) was added to 200 ml of water and the pH of the solution was adjusted to 8.5 using 50% aqueous sodium hydroxides. 37% Formaldehyde (30 ml) was added and the solution allowed stirring 12 hrs. The reaction mixture was acidified to pH 1 with 37% hydrochloric acid and concentrated in vacuo to dryness. The residue was extracted with 2×200 ml of isopropanol at 90° C. The isopropanol extracts were combined and concentrated to yield the crude product (2) (55.4 g, 92%). Recrystallisauon from isopropanol afforded the analytically pure compound as colourless needles. m.p. 160-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[CH:7][C:3]=1C(O)=O.[N-:18]=[N+]=[N-].[Na+]>OS(O)(=O)=O>[NH2:18][C:3]1[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=1[Cl:1])[CH2:11][NH:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(O)c1cc(CNC(=O)C2CC2)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1cc(CNC(=O)C2CC2)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoic acid (5.0 g, 19 mmol) in conc. H2SO4 (30 mL) was added NaN3 (1.4 g, 21 mmol) lotwise at 50° C. The reaction mixture was stirred at 50° C. for 18 h. The reaction mass was quenched with ammonia and ice water. The solid obtained was filtered and suck dried to afford 3.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.66 (m, 4H), 1.56 (m, 1H), 4.12 (d, J=6.0 Hz, 2H), 5.27 (s, 2H), 6.41 (d, J=6.9 Hz, 1H), 6.61 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 8.48 (m, 1H); MS (m/z): 225.22 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11](CBr)[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[SH:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].[CH2:24]1CCN2C(=NCCC2)CC1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:24]=2)[S:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC1(c2cccc(CBr)c2)CCOCC1
Reactant: COC(=O)CCS
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCSC(c1ccccc1)C1(OC)CCOCC1
Temperature: 5 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
A solution of 3-[(4-methoxy)tetrahydropyran-4-yl)-α-bromotoluene (1.0 g, 3.87 mmol) in 10 mL of anhydrous THF was cooled to 5° C. A solution of methyl 3-mercaptopropionate (0.46 g, 3.87 mmol) and DBU (0.59 g, 3.87 mmol) in 10 mL of THF was added while maintaining the temperature at 5° C. The reaction mixture was stirred for 1 h at 5° C. and for 18 h at room temperature. The reaction mixture was diluted with 200 mL of ethyl acetate, and this solution was washed with 1 N HCl (1×100 mL), saturated sodium bicarbonate (1×100 mL), brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to give 0.94 g (75%) of methyl 3-[[(4-methoxy)-tetrahydro-pyran-4-yl]phenylmethylthio]propionate as a pink oil: 1H NMR (CDCl3/300 MHz) δ 1.93–2.09 (m, 4H), 2.54 (t, 2H, J=7.4 Hz), 2.68 (t, 2H, J=7.5 Hz), 2.97 (s, 3H), 3.68 (s, 3H), 3.75 (s, 2H), 3.80–3.92 (m, 4H), 7.23–7.36 (m, 4H). HRMS calcd for C17H24O4S 325.1474. Found 325.1494.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([O-])=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:1][C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[CH:5][N:6]([C:11]5[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=5)[N:7]=4)[CH:3]=3)=[O:31])=[CH:33][CH:34]=2)[CH2:24][CH2:25]1
Reactant: CC(=O)c1ccc(-n2cc3cc(N)ccc3n2)cc1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: CC(=O)c1ccc(-n2cc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc3n2)cc1

Procedure:
Compound 542 was prepared according to the procedure described in Scheme IV from 5-amino-2-(4-acetylphenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C26H24N4O3: 441.18; found: 441.02.